This research program is focused on characterizing the genetic interactions that mediate fatal disease in the lupus-prone NZM2410 mouse model of SLE. During the previous grant period, we identified four suppressive modifiers and two epistatic susceptibility loci that impacted disease development in our B6-congenic model of lupus autoimmunity. We subsequently produced a collection of B6-congenic strains carrying these disease-enhancing or disease-suppressing genes and initiated a detailed characterization of their component phenotypes and epistatic interactions. These experiments have led to the development of a model proposing that severe disease is mediated by epistatic interactions among genes in three separate pathways, each impacting a distinct element of disease pathogenesis {Wakeland, Liu, et al. 2001 2262/id}. In this application, we are proposing to identify three of the genes that were detected in our genetic dissection of this epistatic disease model. The identification of these genes will provide insights into genetic mechanisms that can suppress the breach in tolerance mediated by Sle1, and will identify genes that exacerbate the severity of glomerulonephritis as a consequence of immune complex deposition. We have three specific aims: 1). To fine map and identify kidney-targeting genes in the Sle1 gene cluster. We have developed a nephrotoxic antisera assay that allows the rapid detection of genes that exacerbate the development of glomerulonephritis (GN) as a consequence of immune complex deposition in the kidney. We propose to utilize this assay to complete the fine mapping and identification of these two genes via positional cloning strategies. 2). To fine map and identify Sles1. Sles1 was the strongest suppressive locus detected in our linkage analysis of disease modifiers in the NZW genome. This gene specifically suppresses the breach in immune tolerance mediated by the Sle1 gene cluster. We have produced a series of congenic recombinants with truncated intervals that will allow the localization of Sles1 into a ~950 Kb genomic interval. We will complete this fine mapping analysis and identify Sles1 3). Characterize the component phenotypes and genetic interactions of Sles2, Sles3, Sles4, and Sle6. We propose to create a series of bi- and tri-congenic strains to assess their impact on disease pathogenesis. The long-term goal of these studies is to characterize the genetic interactions that enhance and suppress lupus pathogenesis.